Amino ethyl ethers of picolinyl carbinols



Patented Aug. 5, 1952 UNITEDIsTAT-Y S Amino Ema. crimes or Pic-mm. E QARBINOLS v v I Robert S. Shelton, Marieinont, and

Charles H.

' Tilford, Silverton, Ohio, assignor's to The Wm.

S. Merrell- Company, Cincinnati, Ohio, a, corporation of Delaware No Drawing. Application April 30, 1941's,"""1.I 7

I Serial No. 24,428

4. Claims. "(or zoo-29s). "a.

a. phenyl a aminoethoxy .2 -methylpicolines,

which may be represented bythe formula JO Ce A RiRi in which R, R1 and Rz 'represent hydrogen or an alkyl group having not morethan three carbon atoms, and in which R, R1 and R2 may be alike or different, or in'which'Ri and'R'z may be joined to form a cyclic structure, as whererN,:R1 and R2 form the piperidine radical. The new compounds are basic, and will ordinarily be used in the form of an acid addition salt, e., as the hydrochloride, hydrobromide, sulfate',"succinate, phosphate, glycolate, acetate, tartrate, l'evulinate, or the like, by oral administration in theform of tablets or other suitable form. .The hydrochlorides and hydrobromides" are white, crystalline materials. The free bases are distillable under vacuumand may be converted to the salts by simple neutralization with the required amount of acid, while the acid addition salts may be converted to the free base by treatment with caustic or carbonated alkali in the usual way.

The new products are conveniently prepared by heating the corresponding phenyl-(Z-picolyl) carbinol with the corresponding amino-alkyl chloride or other salt in the presence of sodium, with purification of the free base product by distillation, or crystallization, or by conversion to a salt followed by crystallization. This will be illustrated by the following examples, but the invention is not limited thereto.

Example I .-A mixture of 54 g. of 30 mesh granular aluminum, 0.5 g. of mercuric chloride, and 5 drops of mercury was stirred in flask at about 125 for a few minutes. To this mixture there was then added 50 g. of 'y-picoline and 50 g. of acetophenone. A vigorous reaction ensued when this mixture was refluxed. Then 600 g. of 'y-picoline was added in one portion followed by the dropwise addition of 388 g. of acetophenone over a period of one hour with stirring and refluxing.". Tliemixturerwas refluxed with stirring for an additional '1248 hours. "acted picoline. then was removed by distillation,

Most of the unreand the residue was taken up in about 509 ml. of toluene. To this with stirring was added 330 g. of potassium hydroxide in 500 ml. of water. The

' aqueous layer was discarded, and the toluene solution was extracted with an excess of 10% hydrochloric acid. The combined acid extracts were made alkaline with 20% potassium hydroxide, after which the precipitated oil was extracted with toluene and fractionally distilled. At 138 142 (0.1;1nm.) 254 g.'-(58%) of carbinol was collected; M. 3770 -71? Q; Thehydrochloride melted 15- 53.5 g. of theaforementioned carbinol was dissolved in 400 ml. of dry toluene. Sodium metal (6 g.) was added and the mixture was refluxed with vigorous stirring for about two hours. Then 35 g. of e-dimethylaminoethyl chloride in 400 ml. of dry toluene was added over a period of an hour, with refluxing continued for from 12 to 16 hours. The cooled reactionmixture was then washed witnwater andrtliea'tedwith 10% hydrochloric aciduntil the -'-stirred mixture was acid to Congo red paper.: Sufficient. saturated sodium bicarbonate solutionwas then added to make the solution alkaline tocongo red. The operation re-' sulted'inmost of the unchanged'carbinol remaininsin he oluene layer, and the amino-ether The aqueous layer was separated, made alkaline with sodium carbonate, extracted with 400 ml. of petroleum ether, and the ether extract fractionally distilled. The a-(Z-dimethylaminoethoxy)-amethyl-a-phenyll-methyl-2-picoline was collected at 152-156" C. (0.1 mm.) and amounted to The monohydrochloride was prepared by dissolving the above aminoether in 50 ml. of ethanol and adding 10 ml. of a 46% alcoholic hydrochloric acid solution. About 3 volumes of dry ether were added; the mixture cooled and filtered. The solid hydrochloride having the formula:

iii- Q melted at 162-16i 0., when recrystallized from an isopropanol-ethyl acetate mixture.

3 Example II.The phenyl-methyl-2-(6-methylpyridyD-carbinol having the structural formula:

was prepared by the procedure similar to that of 1 Example I, using 430 g. of a-picoline. The carbinol was collected at 134-136 (0.4 mm.) and its hydrochloride melted at 1125-427 C. and was hygroscopic.

The aminoether having the formula:

o-mm-Nwm),

was prepared from 30 g. of the above carbinol by the etherification procedure described in Example I. The product was collected at 145-150 C. (0.3 mm). Its monohydrochloride melted at 153-155 C.

Example III.The phenyl-2-(4 methylpyridyl) -carbinol having the structure:

1 am OBI-H was prepared by a procedure similar to that of Example I, using benzaldehyde in place of acetophenone. The carbinol was collected during distillation at 136-140 C. (0.1 mm.).

was prepared from this carbinol by the etheriflcation procedure given in Example I. The base was collected at 145-147" (0.07 mm.) and its monohydrochloride melted at 188-190 C.

These compounds are highly eflective as histamine antagonists, and are useful in the treatment of hay-fever, asthma, urticaria, and other ailment of the character associated with physi- 4 ological reactions to histamine or the like, i. e., the so-called allergic responses or syndromes. Other compounds included in the invention and useful for the same purposes include:

a- (2' diethylaminoethoxy) -a-methyl-a-phenyl- 4-methyl-2-picoline;

a-(2'-methylpropylaminoethoxy) a phenyl-6- methyl-Z-picoliue;

a-(Z' dimethylaminoethoxy) -a-phenyl-a-ethyl- 4-methyl-2-picoline;

a. (2' aminoethoxy) a. phenyl a propyl-fimethyl-Z-picoline;

a-(Z' piperidinoethoxy)-a-phenyl-a-methyl-4- methyl-2-picoline.

We claim: 1. Compounds of the formula REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Martin et al Apr. 2, 1946 OTHER REFERENCES J. Chem. Soc., 1939, 809-812.

Chemical Abstracts 35,4!771 (1941), citing Rec. Trav. Chim. 59, 971-977 (1940) 1 Hartman, California Medicine 66 (N0. 4), 242- 248 (1947).

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1. COMPOUNDS OF THE FORMULA 